PROJECT SUMMARY Radiation therapy plays a key role in the treatment of many cancers. Despite its widespread use, we cannot currently identify the patients most likely to benefit from this form of treatment. Neuroblastoma is a malignancy that occurs predominantly in young children. Patients with high-risk disease are treated with maximally intensive therapy, however survival rates for newly diagnosed patients remain poor. Neuroblastoma is sensitive to radiation, and the targeted radiopharmaceutical 131I-metaiodobenzylguanidine (131I-MIBG) is active in this disease. 131I-MIBG is being evaluated in a randomized Phase III trial as a component of frontline treatment for children with high-risk neuroblastoma (Children's Oncology Group ANBL1531). Preliminary studies suggest that tumor and host markers may predict clinical outcomes after 131I-MIBG. As part of ANBL1531, we will evaluate biomarkers that may identify patients most likely to experience a survival advantage after treatment, and could help to identify those patients most likely to experience toxicity related to 131I-MIBG therapy. To evaluate potential biomarkers that could aid in selection of patients for 131I-MIBG therapy, we propose two specific aims. In Aim 1, we will study features of neuroblastoma tumors that may predict outcome after 131I- MIBG. We will assess expression of transporter proteins in tumors from patients treated with and without 131I- MIBG, using specimens obtained at diagnosis and at the time of definitive surgery. In addition, we will evaluate the mutation status and the expression of genes related to neuroblastoma biology and radiation sensitivity. In Aim 2, we will evaluate host factors that may influence survival and toxicity related to 131I-MIBG therapy. We will use normal tissue (blood cells) from patients treated with and without 131I-MIBG to look for mutations that may underlie differences in sensitivity to radiation. In addition, we will study changes in expression of relevant genes in blood samples taken before and after 131I-MIBG exposure to elucidate the basis for differential radiation effects among patients. At the end of this project, we will have identified biomarkers that can be used to select patients with neuroblastoma who are most likely to benefit from 131I-MIBG therapy. Our work may result in improved therapy selection for patients with other cancers and improved understanding of differential clinical responses to therapeutic radiation.